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Preparation method of hydroxypiperaquine and phosphate thereof

A technology of hydroxypiperaquine and hydroxypiperquine phosphate, applied in the field of medicine, can solve the problems of low yield, few reports on the synthesis method of hydroxypiperaquine, inability to obtain hydroxypiperaquine, etc., and achieves a simple preparation method, low cost, and ease of use. effect of operation

Active Publication Date: 2015-12-02
上海博速医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the structure of hydroxypiperaquine is similar to that of piperaquine, the synthetic method of piperaquine cannot obtain hydroxypiperaquine, or the yield is extremely low
And in the prior art, for the synthetic method of hydroxypiperaquine and its phosphate seldom reported

Method used

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  • Preparation method of hydroxypiperaquine and phosphate thereof
  • Preparation method of hydroxypiperaquine and phosphate thereof
  • Preparation method of hydroxypiperaquine and phosphate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] In the present embodiment, hydroxypiperaquine and hydroxypiperaquine phosphate are prepared by the following method, comprising the following steps:

[0065] (1) Synthesis of 1,3-dipiperazinyl propanol

[0066] Add 400 g of ethanol, 129 g (1 mol) of 1,3-dichloropropanol and 173 g (2 mol) of piperazine to the reaction flask. After dissolving, slowly add 88 g (2.2 mol) of acid-binding agent sodium hydroxide, and then react at 90°C 3h. After the reaction, cool down to room temperature, remove the formed inorganic salt by filtration, and remove the solvent under reduced pressure to obtain 210 g of 1,3-dipiperazinylpropanol (92.1% yield) with a melting point of 128°C.

[0067] The proton nuclear magnetic resonance spectrum characterization result of step (1) product is: 1 HNMR (CDCl 3 )δppm: 1.54(1H), 19.1(2H), 2.37(8H), 2.46(4H), 2.65(8H).

[0068] (2) synthetic hydroxypiperaquine

[0069] Add 1054g ethanol, 351.4g (1.774mol) 4,7-dichloroquinoline and 200g (0.877mol) 1...

Embodiment 2

[0075] In the present embodiment, hydroxypiperaquine and hydroxypiperaquine phosphate are prepared by the following method, comprising the following steps:

[0076] (1) Synthesis of 1,3-dipiperazinyl propanol

[0077] Add 1075g water, 64.5g (0.5mol) 1,3-dichloropropanol and 215g (2.5mol) piperazine in reaction bottle, after treating to dissolve, slowly add 80g (2mol) acid-binding agent sodium hydroxide, then in 50 ℃ reaction 7h. After the reaction, cool down to room temperature, remove the formed inorganic salt by filtration, and remove the solvent under reduced pressure to obtain 104.3 g of 1,3-dipiperazinylpropanol (91.5% yield) with a melting point of 128°C.

[0078] The proton nuclear magnetic resonance spectrum characterization result of step (1) product is: 1 HNMR (CDCl 3 )δppm: 1.54(1H), 19.1(2H), 2.37(8H), 2.46(4H), 2.65(8H).

[0079] (2) synthetic hydroxypiperaquine

[0080] Add 261g of acetonitrile, 260.2g (1.314mol) of 4,7-dichloroquinoline and 100g (0.438mol) ...

Embodiment 3

[0086] In the present embodiment, hydroxypiperaquine and hydroxypiperaquine phosphate are prepared by the following method, comprising the following steps:

[0087] (1) Synthesis of 1,3-dipiperazinyl propanol

[0088] Add 172g of water, 64.5g (0.5mol) of 1,3-dichloropropanol and 172g (2mol) of piperazine to the reaction flask. After dissolving, slowly add 159g (1.5mol) of acid-binding agent sodium carbonate, and then Reaction 6h. After the reaction, cool down to room temperature, remove the formed inorganic salt by filtration, and remove the solvent under reduced pressure to obtain 106.2 g of 1,3-dipiperazinylpropanol (93.2% yield) with a melting point of 128°C.

[0089] The proton nuclear magnetic resonance spectrum characterization result of step (1) product is: 1 HNMR (CDCl 3 )δppm: 1.54(1H), 19.1(2H), 2.37(8H), 2.46(4H), 2.65(8H).

[0090] (2) synthetic hydroxypiperaquine

[0091] Add 500g of propanol, 216.8g (1.095mol) of 4,7-dichloroquinoline and 100g (0.438mol) of ...

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Abstract

The invention provides a preparation method of hydroxypiperaquine and phosphate thereof. The preparation method of hydroxypiperaquine comprises the following steps: by using piperazine, 1,3-dihalopropanol and 4,7-dichloroquinoline as raw materials, reacting the piperazine and 1,3-dihalopropanol by using an acid-binding agent as a catalyst to obtain 1,3-dipiperazinylpropanol, carrying out condensation reaction on the 1,3-dipiperazinylpropanol and 4,7-dichloroquinoline under the catalytic action of an alkali to obtain the hydroxypiperaquine. The obtained hydroxypiperaquine reacts with phosphoric acid to obtain the hydroxypiperaquine phosphate. The method has the advantages of mild reaction conditions, simple preparation technique and low cost, and is suitable for industrial production. The total reaction yield of the hydroxypiperaquine is up to 90-91.5%, and the total reaction yield of the hydroxypiperaquine phosphate is up to 82.7-87.5%.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a preparation method of hydroxypiperaquine and its phosphate. Background technique [0002] Hydroxypiperaquine is an excellent drug for treating malaria, and its drug resistance and drug resistance are far superior to other antimalarial drugs. Malaria is a global acute parasitic infectious disease caused by Plasmodium. Worldwide, there are between 300 million and 500 million cases of clinical symptoms every year, and the number of deaths due to malaria is between one and three hundred every year. among ten thousand people. With the use of antimalarial drugs, malaria also develops drug resistance. In addition, studies have shown that hydroxypiperaquine can also treat pneumoconiosis. [0003] Regarding the synthesis of piperaquine, U.S. Patent No. 3,173,918 discloses three synthetic methods: (1) carry out condensation reaction under the catalysis of phenol with 4,7-dichloroquinoline and 1,3...

Claims

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Application Information

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IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 张李锋蔡建萍方瑛陈曾飞
Owner 上海博速医药科技有限公司
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